EP3643309B1 - Nintedanib for use in the treatment of systemic scleroderma - Google Patents

Nintedanib for use in the treatment of systemic scleroderma

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Publication number
EP3643309B1
EP3643309B1 EP19209457.1A EP19209457A EP3643309B1 EP 3643309 B1 EP3643309 B1 EP 3643309B1 EP 19209457 A EP19209457 A EP 19209457A EP 3643309 B1 EP3643309 B1 EP 3643309B1
Authority
EP
European Patent Office
Prior art keywords
amino
phenyl
chinazoline
methoxy
chlor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP19209457.1A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP3643309A1 (en
Inventor
John Edward Park
Armin Heckel
Matthias Grauert
Georg Dahmann
Trixi Brandl
Nveed Chaudhary
Gerald Roth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=36602118&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP3643309(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Publication of EP3643309A1 publication Critical patent/EP3643309A1/en
Application granted granted Critical
Publication of EP3643309B1 publication Critical patent/EP3643309B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Definitions

  • the present invention relates to 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone (compound (u)), the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, particularly the monoethanesulfonate salt thereof, for use in the prevention or treatment of systemic scleroderma.
  • Remodeling is a normal response to tissue injury and inflammation that is observed in many tissues throughout the body. After resolution of the inflammation and repair of tissue damage, the tissue is generally returned to its original condition. Excessive uncontrolled tissue repair or the failure to stop remodeling when it is no longer required leads to condition known as fibrosis. Fibrosis is characterized by excessive deposition of extracellular matrix components and overgrowth of fibroblasts.
  • Fibrosis can occur in all tissues but is especially prevalent in organs with frequent exposure to chemical and biological insults including the lung, skin, digestive tract, kidney, and liver ( Eddy, 1996, J Am Soc Nephrol, 7(12):2495-503 ; Dacic et al., 2003, Am J Respir Cell Mol Biol, 29S: S5-9 ; Wynn, 2004, Nat Rev Immunol, 4(8):583-94 ). Fibrosis often severely compromises the normal function(s) of the organ and many fibrotic diseases are, in fact, life-threatening or severely disfiguring, such as idiopathic pulmonary fibrosis (IPF), liver cirrhosis, scleroderma, or renal fibrosis. Treatment options for these diseases are often limited to organ transplantation, a risky and expensive procedure.
  • IPF idiopathic pulmonary fibrosis
  • PDGF platelet-derived growth factor
  • FGF fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • EGF epidermal growth factor
  • TGFb transforming growth factor beta growth factor families in the induction or persistence of fibrosis
  • PDGF, EGF and FGF family members are potent mitogens for mesenchymal cells such as smooth muscle cells, myofibroblasts and fibroblasts ( Benito et al., 1993, Growth Regul 3(3):172-9 ; Simm et al, 1998, Basic Res Cardiol, 93(S3):40-3 ; Klagsburn, Prog Growth Factor Res, 1989, 1(4):207-35 ; Kirkland et al., 1998, J Am Soc Nephrol, 9(8):1464-73 ), the very cells which supplant normal tissue in fibrosis and are believed to play a role in tissue remodeling ( Abboud, 1995, Annu Rev Physiol., 57:297-309 ; Jinnin et al., 2004, J Cell Physiol, online ; Martinet et al., 1996, Arch Toxicol 18:127-39 ; Desmouliere, Cell Biology International, 1995, 19:471-6 ; Jelaska et al., Springer
  • FGF1/FGF2-deficient mice show dramatically decreased liver fibrosis after chronic carbon tetrachloride (CC14) exposure ( Yu et al., 2003, Am J Pathol, 163(4):1653-62 ).
  • FGF expression is increased in human renal interstitial fibrosis where it strongly correlates with interstitial scarring ( Strutz et al., 2000, Kidney Intl, 57:1521-38 ) as well as in a model of experimental lung fibrosis ( Barrios et al., 1997, Am J Physiol, 273 (2 Pt 1):L451-8 ), again lending credence to the idea that fibrosis in various tissues has a common basis.
  • VEGF vascular endothelial growth factor
  • TGFb stimulates production of extracellular matrix proteins including fibronectin and collagens and is believed to play an important role in fibrosis in many tissues ( Leask et al., 2004, FASEB J 18(7):816-27 ; Bartram et al., 2004, Chest 125(2):754-65 ; Strutz et al., 2003, Springer Semin Immunopathol, 24:459-76 ; Wynn, 2004, Nat Rev Immunol, 4(8):583-94 ).
  • Inhibitors of TGFb production and signaling pathways are active in a number of fibrosis animal models ( Wang et al., 2002, Exp Lung Res, 28:405-17 ; Laping, 2003, Curr Opin Pharmacol, 3(2):204-8 ).
  • the present invention thus relates to 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone (compound (u)), the tautomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the monoethanesulfonate salt thereof, for use in the treatment or prevention of systemic scleroderma.
  • the present invention further relates to compound (u) or its monoethanesulfonate salt for the use mentioned above in combination with a further pharmacologically active substance selected from the group consisting of anticholinergicagents, beta-2 mimetics, steroids, PDE-IV inhibitors, p38 MAP kinase inhibitors, NK1 antagonists, LTD4 antagonists,EGFR inhibitors and endothelin-antagonists.
  • a further pharmacologically active substance selected from the group consisting of anticholinergicagents, beta-2 mimetics, steroids, PDE-IV inhibitors, p38 MAP kinase inhibitors, NK1 antagonists, LTD4 antagonists,EGFR inhibitors and endothelin-antagonists.
  • Tautomers, stereoisomers or physiologically acceptable salts of example (u) are also contemplated within the scope of the present invention, and may be obtained using the methods described in WO 01/27081 .
  • a particularly preferred compound for use according to the invention is the monoethanesulphonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, disclosed for example in WO 04/13099 .
  • the compound (u), its tautomers, its stereoisomers or the physiologically acceptable salts thereof are thus suitable for the prevention or treatment of systemic scleroderma.
  • Example B1 In the following experiments of Example B1, Example A denotes the compound 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, which is compound (m) of the list of the preferred compounds.
  • Bleomycin sulfate (Bleomycin HEXAL TM ) was purchased from a local pharmacy.
  • the lung tissues fixed in 4% formalin were embedded into paraffin and 5 ⁇ m sections were cut using a microtome (Leica SM200R) and placed on poly-L-lysine coated slides. The sections were then dried onto the slides (60°C 2 hours) and then left to cool at room temperature. Collagen deposition was assessed using Masson's Trichrome staining.
  • Figure 1A shows the result obtained with the control group, which received saline and the vehicle instead of bleomycin intratracheally.
  • the alveoli have been largely replaced by fibroblasts and extracellular matrix and the normal lung structure is nearly obliterated.
  • Example A Compound (m)
  • FIG. 1C Alveoli are intact and little or no fibroblast infiltration or extracellular matrix deposition has occurred. Normal lung structure has been maintained, which is evidenced by a comparison of Figure 1C with Figure 1A .
  • the supernatant was then removed and 500 ⁇ l of 70% ethanol was added to wash the pellet then the sample was centrifuged for 10 minutes at 12000 rpm an 4°C, this wash step was repeated twice, after which the pellet was left to dry for 10 - 15 minutes. Finally the pellet was resuspended in 20 ⁇ l RNase free water and stored at -80°C. The concentration of each sample was then measured using a spectrophotometer.
  • RNA sample was reversed transcribed using a modified version of the manufacturer's protocol. Briefly, a mixture of 2 ⁇ g RNA, 1 ⁇ l random hexamer primers (50ng/ ⁇ l), 1 ⁇ l dNTP mix (10mM) was made up to 10 ⁇ l with DEPC-treated water and incubated at 65°C for 5 minutes, after which it was placed on ice for 5 minutes.
  • Real Time PCR was carried out in 25 ⁇ l reactions, using 25ng (5 ⁇ l) of cDNA per reaction.
  • a quantitative PCR core kit was purchased (Eurogentec) and a master-mix was made up as follows for 100 reactions: 500 ⁇ l 10X reaction buffer, 500 ⁇ l MgCl 2 (50mM), 200 ⁇ l dNTP mix solution (5mM), 25 ⁇ l Hot Goldstar enzyme, 75 ⁇ l 18S PDAR, 22.5 ⁇ l forward primer, 22.5 ⁇ l reverse primer, 15 ⁇ l probe and 640 ⁇ l DEPC treated water. 20 ⁇ l of this master-mix was then added to 25ng (5 ⁇ l) target cDNA. Each analysis was carried out in triplicate.
  • a standard curve was constructed for each primer set and was included on each plate.
  • the standards were made up of a mix of all the cDNA's under investigation; this mix of cDNA's was serially diluted 10, 20, 50, 100, 100 times.
  • a standard curve was constructed of the obtained C T (Cycle at which amplification reaches a set Threshold) against the LOG 10 of the dilution factor. Curves were drawn for the target gene and the 18S rRNA endogenous control. The C T value for both targets for each of the samples was then converted to a fold dilution using the standard curve and the target gene value was normalized to the 18S gene value.
  • Example A Compound (m) showed a significant (p ⁇ 0.0001) inhibition of expression of fibrotic marker genes in this model, as seen in Figures 2 and 3 .
  • Figure 4A shows the result obtained with the control group, which received saline and the vehicle instead of bleomycin intratracheally.
  • the alveoli have been largely replaced by fibroblasts and extracellular matrix and the normal lung structure is nearly obliterated.
  • the compounds according to the invention may be used in monotherapy or in conjunction with other pharmacologically active compounds.
  • pharmacologically active compounds may be compounds which are, for example, also pharmacologically active in the treatment of fibrosis.
  • pharmacologically active compounds may also be substances with a secretolytic, broncholytic and/or anti-inflammatory activity.
  • such pharmacologically active compounds are preferably selected from the group consisting of anticholinergic agents, beta-2 mimetics, steroids, PDE-IV inhibitors, p38 MAP kinase inhibitors, NK 1 antagonists, LTD4 antagonists, EGFR inhibitors and endothelin-antagonists.
  • Anticholinergic agents may preferably be selected from the group consisting of the tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts and trospium salts.
  • Beta-2 mimetics may preferably be selected from the beta-2 mimetics disclosed, for example, in US 4,460,581 , which is incorporated herein by reference.
  • PDE-IV inhibitors may preferably be selected from the group consisting of enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, pumafentine, (-)p-[(4 a R*,10 b S*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide, (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyl
  • These compounds may be used, as available, in the form of their racemates, enantiomers or diastereoisomers, or in the form of pharamacologically acceptable acid addition salts thereof, or in the form of their solvates and/or hydrates.
  • Steroids may preferably be selected from the group consisting of prednisolone, prednisone, butixocortpropionate, RPR-106541, flunisolid, beclomethasone, triamcinolone, budesonid, fluticasone, mometasone, ciclesonid, rofleponid, ST-126, dexamethasone, 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-dien-17 ⁇ -carbothionic acid (S)-fluoromethylester, and 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -propionyloxy-androsta-1,4-diene-17 ⁇ -carbothionic acid (S)-(2-oxo-tetrahydro-furan-3S-yl)ester.
  • These compounds may be used, as available, in the form of their racemates, enantiomers or diastereoisomers, or in the form of pharamacologically acceptable acid addition salts thereof, or in the form of their solvates and/or hydrates.
  • p38 MAP kinase inhibitors may preferably be selected from the group consisting of the p38 Kinase inhibitors that are disclosed for instance in US Patents 5,716,972 , US 5,686,455 , US 5,656,644 , US 5,593,992 , US 5,593,991 , US 5,663,334 , US 5,670,527 , US 5,559,137 , 5,658,903 , US 5,739,143 , US 5,756,499 , US 6,277,989 , US 6,340,685 , and US 5,716,955 and PCT applications WO 92/12154 , WO 94/19350 , WO 95/09853 , WO 95/09851 , WO 95/09847 , WO 95/09852 , WO 97/25048 , WO 97/25047 , WO 97/33883 , WO 97/35856 , WO 97/35855 ,
  • NK 1 antagonists may preferably be selected from the group consisting of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2- ⁇ 4-cyclopropylmethyl-piperazin-1-yl ⁇ -N-methyl-2-phenyl-acetamide (BIIF 1149), CP-122721, FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968 (Saredutant), SR 140333 (Nolpitantium besilate/chloride), LY 303 870 (Lanepitant), MEN-11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, SR-144190, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018
  • LTD4 antagonists may preferably be selected from the group consisting of montelukast, 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetate, 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetate, pranlukast, zafirlukast, [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetate, MCC-847 (ZD-3523), MN-001
  • These compounds may be used, as available, in the form of their racemates, enantiomers or diastereoisomers, or in the form of pharamacologically acceptable acid addition salts thereof, or in the form of their solvates and/or hydrates.
  • EGFR inhibitors may preferably be selected from the group consisting of 4-[(3-chlor-4-fluorphenyl)amino]-6- ⁇ [4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino ⁇ -7-cyclopropylmethoxy-chinazoline, 4-[(3-chlor-4-fluorphenyl)amino]-6- ⁇ [4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino ⁇ -7-cyclopropylmethoxy-chinazoline, 4-[(3-chlor-4-fluorphenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino ⁇ -7-cyclopropylmethoxy-chinazoline, 4-[( R )-(1-phenyl-ethyl)amino]-6- ⁇ [4-(morpholin
  • Endothelin-antagonists may preferably be selected from the group consisting of tezosentan, bosentan, enrasentan, sixtasentan, T-0201, BMS-193884, K-8794, PD-156123, PD-156707, PD-160874, PD-180988, S-0139 and ZD-1611.
  • Any reference to endothelin-antagonists within the scope of the present invention includes a reference to the salts, preferably pharmacologically acceptable acid addition salts, or derivatives which may be formed from the endothelin-antagonists.
  • the compounds according to the invention are preferably used for warm-blooded vertebrates, particularly humans, in doses of 0.0001-100 mg/kg of body weight.
  • These compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation, or transdermally, or orally, whilst aerosol formulations are particularly suitable for inhalation.
  • inert solid, semisolid or liquid carriers e.g. with starch, different types of cellulose, lactose, mannitol, sorbitol, glucose, calcium phosphate, hard fat, fatty alcohols, glycerol, medium chained triglycerides and related esters, polyethylene glycol, refined specialty oils, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, and/or functional excipients, e.g.
  • polyvinylpyrrolidone hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium starch glycolate, silicon dioxide, polysorbates, poloxamers, gelucires, magnesium stearate, citric acid, tartaric acid, or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, injectable solutions, ampoules, suspensions, solutions, sprays or suppositories.
  • Example F1 Coated tablet containing 75 mg of active substance
  • 1 tablet core contains:
  • active substance 75.0 mg calcium phosphate 131.0 mg polyvinylpyrrolidone 10.0 mg carboxymethylcellulose sodium 10.0 mg silicon dioxide 2.5 mg magnesium stearate 1.5 mg 230.0 mg
  • the active substance is mixed with all components, sieved and compressed in a tablet-making machine to form tablets of the desired shape.
  • Weight of core 230 mg
  • Appearance of core 9 mm, biconvex
  • the tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. Weight of coated tablet: 240 mg.
  • Example F2 Tablet containing 100 mg of active substance
  • 1 tablet contains:
  • the active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the hydroxypropylmethylcellulose. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50°C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets. Weight of tablet: 220 mg Appearance of tablet: 10 mm, flat faced with bevelled edges and breaking notch on one side.
  • Example F3 Tablet containing 150 mg of active substance
  • 1 tablet contains:
  • the active substance mixed with lactose, polyvinylpyrrolidone, and parts of the microcrystalline cellulose, magnesium stearate is compacted e.g. on a roller compactor.
  • the ribbons are broken up in fine granules through a screen with a mesh size of 0.8 mm. After subsequent sieving through a screen with a mesh size of 0.5 mm and blending with the remaining components, tablets are pressed from the mixture.
  • Appearance of tablet 10 mm, flat
  • Example F4 Hard gelatine capsule containing 150 mg of active substance
  • 1 capsule contains:
  • lactose 85.0 mg microcrystalline cellulose 40.0 mg polyvinylpyrrolidone 10.0 mg silicon dioxide 10.0 mg magnesium stearate 5.0mg 300.0 mg
  • the active substance mixed with lactose, polyvinylpyrrolidone, and parts of the microcrystalline cellulose, magnesium stearate is compacted e.g. on a roller compactor.
  • the ribbons are broken up in fine granules through a screen with a mesh size of 0.8 mm. After subsequent sieving through a screen with a mesh size of 0.5 mm and blending with the remaining components, the finished mixture is packed into size 1 hard gelatine capsules.
  • Capsule shell size 1 hard gelatine capsule.
  • Example F5 Suppository containing 150 mg of active substance
  • 1 suppository contains:
  • the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.
  • Example F6 Suspension containing 50 mg of active substance
  • active substance 1.00 g carboxymethylcellulose sodium 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 ml
  • the distilled water is heated to 70°C.
  • the methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring.
  • the solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring.
  • the suspension is evacuated with stirring to eliminate air.
  • 5 ml of suspension contains 50 mg of active substance.
  • Example F7 Ampoule containing 10 mg active substance
  • the active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with sodium chloride, filtered sterile and transferred into a 2 ml ampoule.
  • Example F8 Ampoule containing 50 mg of active substance
  • the active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with sodium chloride, filtered sterile and transferred into a 10 ml ampoule.
  • Example F9 Capsule for powder inhalation containing 5 mg of active substance
  • the active substance is mixed with lactose for inhalation.
  • the mixture is packed into capsules in a capsule-making machine (weight of the empty capsule approx. 50 mg).
  • Example F10 Solution for inhalation for a hand-held nebuliser containing 2.5 mg active substance
  • the active substance and benzalkonium chloride are dissolved in ethanol/water (50/50).
  • the pH of the solution is adjusted with 1N hydrochloric acid.
  • the resulting solution is filtered and transferred into suitable containers for use in hand-held nebulisers (cartridges). Contents of the container: 4.5 g

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Families Citing this family (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060154939A1 (en) * 2004-12-24 2006-07-13 Boehringer Ingelheim International Gmbh Medicaments for the Treatment or Prevention of Fibrotic Diseases
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
US20100184747A1 (en) * 2007-06-12 2010-07-22 Boehringer Ingelheim International Gmbh Indoline derivatives and their use in treating disease-states such as cancer
DK2170827T3 (da) 2007-06-21 2013-11-18 Janssen Pharmaceutica Nv Indolin-2-oner og aza-indolin-2-oner
MY158929A (en) 2008-06-06 2016-11-30 Boehringer Ingelheim Int Pharmaceutical combination
EP2299987B1 (en) 2008-06-06 2018-02-21 Boehringer Ingelheim International GmbH Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative
UA107560C2 (uk) * 2008-06-06 2015-01-26 Фармацевтична лікарська форма для негайного вивільнення похідної індолінону
AU2015227503B2 (en) * 2008-06-06 2017-02-23 Boehringer Ingelheim International Gmbh Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative
US20170065529A1 (en) 2015-09-09 2017-03-09 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
JP5651110B2 (ja) * 2008-07-29 2015-01-07 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規化合物
US8802384B2 (en) * 2009-03-12 2014-08-12 Boehringer Ingelheim International Gmbh Method or system using biomarkers for the monitoring of a treatment
WO2010130758A1 (en) * 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh New combination therapy in treatment of cancer and fibrotic diseases
EP2647375A1 (en) * 2009-05-14 2013-10-09 Boehringer Ingelheim International Gmbh Combination of vargatef and dabigatran for the treatment of oncological and fibrotic diseases
US20120107304A1 (en) 2010-04-27 2012-05-03 Boehringer Ingelheim International Gmbh Combination therapy in treatment of oncological and fibrotic diseases
US8381108B2 (en) 2010-06-21 2013-02-19 Microsoft Corporation Natural user input for driving interactive stories
WO2012021974A1 (en) 2010-08-20 2012-02-23 The Hospital For Sick Children Compositions and methods for treatment of cystic fibrosis and diseases associated with aberrant protein cellular processing
CN103102352B (zh) * 2011-11-15 2015-08-12 山东亨利医药科技有限责任公司 酪氨酸激酶抑制剂吲哚满酮衍生物
CN103130775B (zh) * 2011-11-22 2015-09-30 山东亨利医药科技有限责任公司 作为酪氨酸激酶抑制剂的吲哚满酮衍生物
EP3604307A1 (en) 2012-01-26 2020-02-05 Angion Biomedica Corp. Anti-fibrotic compounds and uses thereof
CN103848814B (zh) * 2012-12-06 2016-08-17 山东亨利医药科技有限责任公司 作为酪氨酸激酶抑制剂的取代吲哚满酮衍生物
US20140350022A1 (en) 2013-05-10 2014-11-27 Boehringer Ingelheim International Gmbh Efficacious treatment of NSCLC and predictive clinical marker of the responsiveness of a tumour to a treatment
CN104003925B (zh) * 2013-06-05 2016-03-30 四川大学 吲哚酮化合物或其衍生物及其用途
WO2015009889A1 (en) * 2013-07-18 2015-01-22 Concert Pharmaceuticals, Inc. Deuterated intedanib derivatives and their use for the treatment of proliferative disorders
JP6799201B2 (ja) 2013-07-31 2020-12-16 アヴァリン ファーマ インク． エアロゾルチロシンキナーゼ阻害剤の化合物、及びその使用
US10450295B2 (en) * 2013-08-09 2019-10-22 Acclaim BioMed USA LLC Method of using an indolinone molecule and derivatives for inhibiting liver fibrosis and hepatitis
WO2015120110A2 (en) 2014-02-07 2015-08-13 Auspex Pharmaceuticals, Inc. Novel pharmaceutical formulations
CN106432042A (zh) * 2015-08-13 2017-02-22 南京华威医药科技开发有限公司 尼达尼布乙磺酸水合物的药物新晶型
CN108367165B (zh) * 2015-10-07 2022-03-04 艾葳生物科技有限公司 治疗皮肤纤维化病症的组合物和方法
MY195904A (en) 2015-12-24 2023-02-27 Respivert Ltd Indolinones Compounds and Their use in the Treatment Of Fibrotic Diseases
CN107019697A (zh) * 2016-02-02 2017-08-08 瑞阳(苏州)生物科技有限公司 预防或治疗纤维化疾病的药物组合物及其应用
JP7039480B2 (ja) 2016-03-08 2022-03-22 レスピバート・リミテツド プロテインキナーゼ阻害剤としてのインドール誘導体およびそれらの使用
WO2017178428A1 (en) 2016-04-13 2017-10-19 Boehringer Ingelheim International Gmbh Pharmaceutical combination of nintedanib, trifluridine and tipiracil for treating colorectal cancer
EP3246029A1 (en) 2016-05-19 2017-11-22 Boehringer Ingelheim International Gmbh Pharmaceutical combination of nintedanib and capecitabine for the treatment of colorectal cancer
WO2017203027A1 (en) 2016-05-27 2017-11-30 Boehringer Ingelheim International Gmbh Use of ecm biomarkers for the determining the treatment onset with nintedanib and pirfenidone
WO2017207643A1 (en) 2016-06-01 2017-12-07 Boehringer Ingelheim International Gmbh Use of ecm biomarkers for the determining the treatment onset with nintedanib and pirfenidone
CN109476594A (zh) * 2016-07-08 2019-03-15 亚利桑那大学董事会 二氢吲哚衍生物及其使用和制备方法
CN108066343A (zh) * 2016-11-08 2018-05-25 瑞阳(苏州)生物科技有限公司 一种预防或治疗肾纤维化疾病的药物
JP2019536812A (ja) * 2016-12-12 2019-12-19 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング オロダテロールとの同時投与による間質性肺疾患の処置方法に使用するためのニンテダニブ
CN106692150B (zh) * 2016-12-21 2019-08-20 中国人民解放军第三〇二医院 尼达尼布在制备预防和治疗肝纤维化与肝硬化的药物中的用途
US20190388407A1 (en) * 2017-02-12 2019-12-26 Aiviva Biopharma, Inc. Multikinase inhibitors of vegf and tfg beta and uses thereof
WO2018177893A1 (en) 2017-03-28 2018-10-04 Boehringer Ingelheim International Gmbh Nintedanib for use in methods for the treatment of muscular dystrophy
WO2019071144A1 (en) 2017-10-05 2019-04-11 Fulcrum Therapeutics, Inc. USE OF P38 INHIBITORS TO REDUCE DUX4 EXPRESSION
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
HRP20251042T1 (hr) * 2017-10-23 2025-10-24 Boehringer Ingelheim International Gmbh Nova kombinacija aktivnih sredstava za liječenje progresivnih intersticijskih bolesti pluća s fibroznim promjenama (pf-ild)
LT3761980T (lt) 2018-03-07 2024-03-12 Pliant Therapeutics, Inc. Aminorūgščių junginiai ir jų panaudojimo būdai
JP7061310B2 (ja) * 2018-04-05 2022-04-28 国立大学法人 大分大学 慢性脂肪性疾患の予防および治療用医薬
CN112004527B (zh) 2018-04-23 2024-09-24 盈擘生技股份有限公司 用于治疗肺部疾病的可吸入脂质体缓释组合物
CN108358827A (zh) * 2018-05-07 2018-08-03 日照市普达医药科技有限公司 一种治疗牛皮癣的2-氧代-吲哚类衍生物及其制备方法
CN120305263A (zh) 2018-06-15 2025-07-15 汉达癌症医药责任有限公司 卡博替尼的盐类于制备治疗癌症的剂型的用途
CA3109703C (en) 2018-08-15 2023-10-17 Aiviva Biopharma, Inc. Multi-kinase inhibitors of vegf and tgf beta and uses thereof
CN109134431B (zh) * 2018-10-10 2021-06-04 成都理工大学 作为囊性纤维化跨膜传导调节因子抑制剂的氨基咪唑偶联吡啶酮衍生物
GB201905371D0 (en) 2019-04-16 2019-05-29 Mission Therapeutics Ltd Novel compounds
GB201905375D0 (en) 2019-04-16 2019-05-29 Mission Therapeutics Ltd Novel compounds
GB201912674D0 (en) 2019-09-04 2019-10-16 Mission Therapeutics Ltd Novel compounds
CN114761001A (zh) 2019-12-04 2022-07-15 爱杜西亚药品有限公司 氮杂环丁烷lpa1受体拮抗剂与抗纤维化药剂的组合
JP2023519600A (ja) 2020-04-01 2023-05-11 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 線維性状態の治療におけるバイオマーカーの使用
BR112022020058A2 (pt) 2020-04-08 2022-11-22 Mission Therapeutics Ltd N-cianopirrolidinas com atividade como inibidores de usp30
GB202006079D0 (en) 2020-04-24 2020-06-10 Vicore Pharma Ab New composition
GB202006074D0 (en) 2020-04-24 2020-06-10 Vicore Pharma Ab New composition
BR112022020644A2 (pt) 2020-05-28 2022-12-06 Mission Therapeutics Ltd Derivados de n-(1-ciano-pirrolidin-3-il)-5-(3-(trifluorometil)fenil) oxazol-2-carboxamida e os correspondentes derivados de oxadiazol como inibidores de usp30 para o tratamento de disfunção mitocondrial
JP7796047B2 (ja) 2020-06-04 2026-01-08 ミッション セラピューティクス リミティド Ｕｓｐ３０阻害剤としての活性を有するｎ－シアノピロリジン
DK4161929T3 (da) 2020-06-08 2025-08-18 Mission Therapeutics Ltd 1-(5-(2-cyanopyridin-4-yl)oxazol-2-carbonyl)-4-methylhexahydropyrrolo[3,4-b]pyrrol-5(1h)-carbonitril som usp30-hæmmer til anvendelse i behandling af mitokondriedysfunktion, cancer og fibrose
GB202016800D0 (en) 2020-10-22 2020-12-09 Mission Therapeutics Ltd Novel compounds
JP2024544660A (ja) 2021-12-01 2024-12-03 ミッション セラピューティクス リミティド Ｕｓｐ３０阻害剤としての活性を有する置換ｎ－シアノピロリジン
JP2025506869A (ja) 2022-02-28 2025-03-13 ナフォーミックス テクノロジーズ リミテッド 特発性肺線維症の処置のための組成物及び方法
WO2024037982A1 (en) 2022-08-16 2024-02-22 Boehringer Ingelheim International Gmbh Pharmaceutical formulations of nintedanib for intraocular use
CN118772038B (zh) * 2023-01-03 2025-07-29 天津征程医药科技有限公司 2-吲哚酮衍生物及其用途
GB202408928D0 (en) 2024-06-21 2024-08-07 Mission Therapeutics Ltd Novel compounds
GB202411060D0 (en) 2024-07-29 2024-09-11 Mission Therapeutics Ltd Novel compounds

Family Cites Families (178)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4460581A (en) 1982-10-12 1984-07-17 Boehringer Ingelheim Kg (1-Hydroxy-2-amino-alkyl)-substituted benzoxazinones and benzoxazolinones
WO1992012154A1 (en) 1990-12-31 1992-07-23 Fujisawa Pharmaceutical Co., Ltd. Imidazotriazine derivatives
GB9816837D0 (en) 1998-08-04 1998-09-30 Zeneca Ltd Amide derivatives
MX9300141A (es) 1992-01-13 1994-07-29 Smithkline Beecham Corp Compuestos de imidazol novedosos, procedimiento para su preparacion y composiciones farmaceuticas que lo contienen.
US5656644A (en) 1994-07-20 1997-08-12 Smithkline Beecham Corporation Pyridyl imidazoles
US5716972A (en) 1993-01-13 1998-02-10 Smithkline Beecham Corporation Pyridyl substituted imidazoles
GB9303993D0 (en) 1993-02-26 1993-04-14 Fujisawa Pharmaceutical Co New heterocyclic derivatives
US5670527A (en) 1993-07-16 1997-09-23 Smithkline Beecham Corporation Pyridyl imidazole compounds and compositions
US5593991A (en) 1993-07-16 1997-01-14 Adams; Jerry L. Imidazole compounds, use and process of making
US5593992A (en) 1993-07-16 1997-01-14 Smithkline Beecham Corporation Compounds
JPH08503971A (ja) 1993-10-01 1996-04-30 チバ−ガイギー アクチェンゲゼルシャフト ピリミジンアミン誘導体及びその調製のための方法
US5543520A (en) 1993-10-01 1996-08-06 Ciba-Geigy Corporation Pyrimidine derivatives
US5728708A (en) 1993-10-01 1998-03-17 Novartis Corporation Pharmacologically active pyridine derivatives and processes for the preparation thereof
ES2262137T3 (es) 1993-10-01 2006-11-16 Novartis Ag Derivados de pirimidinamina farmacologicamente activos y procedimientos para su preparacion.
GB9401182D0 (en) 1994-01-21 1994-03-16 Inst Of Cancer The Research Antibodies to EGF receptor and their antitumour effect
US5559137A (en) 1994-05-16 1996-09-24 Smithkline Beecham Corp. Compounds
DE69536015D1 (de) 1995-03-30 2009-12-10 Pfizer Prod Inc Chinazolinone Derivate
TW449590B (en) 1995-04-14 2001-08-11 Boehringer Ingelheim Kg New arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds
IL118544A (en) 1995-06-07 2001-08-08 Smithkline Beecham Corp History of imidazole, the process for their preparation and the pharmaceutical preparations containing them
US5739143A (en) 1995-06-07 1998-04-14 Smithkline Beecham Corporation Imidazole compounds and compositions
US5880141A (en) * 1995-06-07 1999-03-09 Sugen, Inc. Benzylidene-Z-indoline compounds for the treatment of disease
EP0836605B1 (en) 1995-07-06 2002-02-06 Novartis AG Pyrrolopyrimidines and processes for the preparation thereof
DE69637948D1 (de) 1995-10-06 2009-07-23 Merck & Co Inc Substituierte imidazole mit krebsremmender und cytokininhibierender wirkung
WO1997016441A1 (en) 1995-10-31 1997-05-09 Merck & Co., Inc. Substituted aryl pyrroles, compositions containing such compounds and methods of use
WO1997016442A1 (en) 1995-10-31 1997-05-09 Merck & Co., Inc. Substituted pyridyl pyrroles, compositions containing such compounds and methods of use
JP2001508395A (ja) 1996-01-11 2001-06-26 スミスクライン・ビーチャム・コーポレイション 新規シクロアルキル置換イミダゾール
AP9700912A0 (en) 1996-01-11 1997-01-31 Smithkline Beecham Corp Novel cycloalkyl substituted imidazoles
TR199801361T2 (xx) 1996-01-11 1998-10-21 Smithkline Beecham Corporation Yeni ikameli imidazol bile�imleri.
ZA97175B (en) 1996-01-11 1997-11-04 Smithkline Beecham Corp Novel substituted imidazole compounds.
DE19608665A1 (de) 1996-03-06 1997-09-11 Boehringer Ingelheim Kg Neue Arylglycinamidderivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen
WO1997033883A1 (en) 1996-03-13 1997-09-18 Smithkline Beecham Corporation Novel pyrimidine compounds useful in treating cytokine mediated diseases
WO1997035855A1 (en) 1996-03-25 1997-10-02 Smithkline Beecham Corporation Novel treatment for cns injuries
WO1997035856A1 (en) 1996-03-25 1997-10-02 Smithkline Beecham Corporation Novel treatment for cns injuries
JP2000504023A (ja) 1996-04-03 2000-04-04 メルク エンド カンパニー インコーポレーテッド 癌治療方法
EP0906307B1 (en) 1996-06-10 2005-04-27 Merck & Co., Inc. Substituted imidazoles having cytokine inhibitory activity
JP2001506230A (ja) 1996-08-09 2001-05-15 スミスクライン・ビーチャム・コーポレイション 新規ピペラジン含有化合物
WO1998007425A1 (en) 1996-08-21 1998-02-26 Smithkline Beecham Corporation Imidazole compounds, compositions and use
DE19633640C2 (de) 1996-08-21 1999-05-06 Ford Global Tech Inc Vorrichtung zur Winkelverstellung einer Welle gegenüber einem Antriebsrad
DE69728688T2 (de) 1996-11-19 2004-08-19 Amgen Inc., Thousand Oaks Aryl und heteroaryl substituierte kondensierte pyrrole als entzündunghemmende mittel
AU730295B2 (en) 1996-11-20 2001-03-01 Merck & Co., Inc. Triaryl substituted imidazoles as glucagon antagonists
HUP0001140A3 (en) 1996-12-05 2002-05-28 Amgen Inc Thousand Oaks Substituted pyrimidinone and pyridone compounds and methods of use
AR038955A1 (es) 1996-12-05 2005-02-02 Amgen Inc Compuestos de pirimidinona y piridona sustituidos y metodos para su uso
ZA9711092B (en) 1996-12-11 1999-07-22 Smithkline Beecham Corp Novel compounds.
US6147080A (en) 1996-12-18 2000-11-14 Vertex Pharmaceuticals Incorporated Inhibitors of p38
JP3573757B2 (ja) 1997-01-29 2004-10-06 ファイザー・インク スルホニルウレア誘導体、およびインターロイキン−１の活性を制御する上でのスルホニルウレア誘導体の使用
CA2297176A1 (en) 1997-04-24 1998-10-29 Ortho-Mcneil Pharmaceutical, Inc. Substituted imidazoles useful in the treatment of inflammatory diseases
WO1998047899A1 (en) 1997-04-24 1998-10-29 Ortho-Mcneil Corporation, Inc. Substituted pyrrolopyridines useful in the treatment of inflammatory diseases
US6235883B1 (en) 1997-05-05 2001-05-22 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
CA2289102A1 (en) 1997-05-07 1998-11-12 Sugen, Inc. 2-indolinone derivatives as modulators of protein kinase activity
US6514977B1 (en) 1997-05-22 2003-02-04 G.D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
JP2002508754A (ja) 1997-05-22 2002-03-19 ジー ディ サール アンド カンパニ ｐ３８キナーゼ阻害剤としての置換基を有するピラゾール類
JP2002502380A (ja) 1997-05-22 2002-01-22 ジー．ディー．サール アンド カンパニー ｐ３８キナーゼ阻害剤としてのピラゾール誘導体
AR037061A1 (es) 1997-05-22 2004-10-20 Searle & Co Compuesto derivado de pirazol sustituido, procesos para preparar dicho compuesto, composicion farmaceutica que lo contiene y su uso en la preparacion de medicamentos
AU7585498A (en) 1997-05-23 1998-12-11 Bayer Corporation Inhibition of p38 kinase activity by aryl ureas
ES2153337T3 (es) 1997-05-23 2008-11-01 Bayer Pharmaceuticals Corporation Inhibidores de la quinasa raf.
EP0988301B1 (en) 1997-06-12 2006-08-09 Aventis Pharma Limited Imidazolyl-cyclic acetals
WO1998056377A1 (en) 1997-06-13 1998-12-17 Smithkline Beecham Corporation Novel pyrazole and pyrazoline substituted compounds
US6093742A (en) 1997-06-27 2000-07-25 Vertex Pharmaceuticals, Inc. Inhibitors of p38
GB9713726D0 (en) 1997-06-30 1997-09-03 Ciba Geigy Ag Organic compounds
US6040320A (en) 1997-06-30 2000-03-21 Ortho-Mcneil Pharmaceutical, Inc. 2-substituted imidazoles useful in the treatment of inflammatory diseases
US5939421A (en) 1997-07-01 1999-08-17 Signal Pharmaceuticals, Inc. Quinazoline analogs and related compounds and methods for treating inflammatory conditions
TW517055B (en) 1997-07-02 2003-01-11 Smithkline Beecham Corp Novel substituted imidazole compounds
AR016294A1 (es) 1997-07-02 2001-07-04 Smithkline Beecham Corp Compuesto de imidazol sustituido, composicion farmaceutica que la contiene, su uso en la fabricacion de un medicamento y procedimiento para supreparacion
WO1999001452A1 (en) 1997-07-02 1999-01-14 Smithkline Beecham Corporation Novel cycloalkyl substituted imidazoles
US5981710A (en) 1997-07-21 1999-11-09 Baxter International, Inc. Therapeutic hemoglobin composition having isotropically increased size
GB9718913D0 (en) * 1997-09-05 1997-11-12 Glaxo Group Ltd Substituted oxindole derivatives
CN1271279A (zh) 1997-09-23 2000-10-25 普尼卡有限公司 用于治疗细胞因子介导性疾病的酰胺类衍生物
US5975738A (en) 1997-09-30 1999-11-02 Lsi Logic Corporation Method for detecting failure in redundant controllers using a private LUN
WO1999017776A1 (en) 1997-10-08 1999-04-15 Smithkline Beecham Corporation Novel cycloalkenyl substituted compounds
EP1031572A4 (en) 1997-11-14 2001-09-19 Sankyo Co PYRIDYLPYRROL DERIVATIVES
US6335340B1 (en) 1997-12-19 2002-01-01 Smithkline Beecham Corporation compounds of heteroaryl substituted imidazole, their pharmaceutical compositons and uses
JP2002515891A (ja) 1997-12-19 2002-05-28 スミスクライン・ビーチャム・コーポレイション 新規なピペリジン含有化合物
WO1999032110A1 (en) 1997-12-22 1999-07-01 Bayer Corporation INHIBITION OF p38 KINASE ACTIVITY USING ARYL AND HETEROARYL SUBSTITUTED HETEROCYCLIC UREAS
ES2154253T3 (es) 1997-12-22 2012-01-27 Bayer Healthcare Llc Inhibición de la actividad de p38 cinasa usando ureas heterocíclicas sustituidas.
WO1999032463A1 (en) 1997-12-22 1999-07-01 Bayer Corporation INHIBITION OF p38 KINASE USING SYMMETRICAL AND UNSYMMETRICAL DIPHENYL UREAS
RS49779B (sr) 1998-01-12 2008-06-05 Glaxo Group Limited, Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze
US6147096A (en) 1998-02-26 2000-11-14 Ortho Mcneil Pharmaceutical, Inc. Substituted pyrrolobenzimidazoles for treating inflammatory diseases
EP1072591A4 (en) 1998-03-26 2005-01-05 Santen Pharmaceutical Co Ltd NEW UREA CONNECTIONS
DE19815020A1 (de) 1998-04-03 1999-10-07 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
DE19816624A1 (de) 1998-04-15 1999-10-21 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
IL139169A0 (en) 1998-05-05 2001-11-25 Hoffmann La Roche Pyrazole derivatives as p-38 map kinase inhibitors
US6316466B1 (en) 1998-05-05 2001-11-13 Syntex (U.S.A.) Llc Pyrazole derivatives P-38 MAP kinase inhibitors
MY132496A (en) 1998-05-11 2007-10-31 Vertex Pharma Inhibitors of p38
JP2002514640A (ja) 1998-05-14 2002-05-21 ジー・ディー・サール・アンド・カンパニー ｐ３８キナーゼ阻害剤としての１，５−ジアリール置換ピラゾール類
CN1188389C (zh) 1998-05-15 2005-02-09 阿斯特拉曾尼卡有限公司 用于治疗由细胞因子引起的疾病的苯甲酰胺衍生物
ES2232137T3 (es) 1998-05-15 2005-05-16 Astrazeneca Ab Derivados de benzamida para el tratamiento de enfermedades mediadas por citoquinas.
US6589954B1 (en) 1998-05-22 2003-07-08 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
KR100605140B1 (ko) 1998-05-22 2006-07-28 싸이오스 인크 심장병 및 다른 질병을 치료하기 위한 헤테로 고리 화합물및 그 치료 방법
NZ526958A (en) 1998-05-22 2004-12-24 Smithkline Beecham Corp Novel 2-alkyl substituted imidazole compounds
US6340685B1 (en) 1998-05-22 2002-01-22 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
EP1082320A4 (en) 1998-05-26 2001-11-21 Smithkline Beecham Corp NEW SUBSTITUTED IMIDAZOLE COMPOUNDS
DE19824922A1 (de) * 1998-06-04 1999-12-09 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
WO1999064400A1 (en) 1998-06-12 1999-12-16 Vertex Pharmaceuticals Incorporated INHIBITORS OF p38
AU4395399A (en) 1998-07-02 2000-01-24 Sankyo Company Limited Five-membered heteroaryl compounds
US6207687B1 (en) 1998-07-31 2001-03-27 Merck & Co., Inc. Substituted imidazoles having cytokine inhibitory activity
CN1142912C (zh) 1998-08-04 2004-03-24 阿斯特拉曾尼卡有限公司 用作细胞因子产生的抑制剂的酰胺衍生物
EP1103543A4 (en) 1998-08-05 2005-06-22 Santen Pharmaceutical Co Ltd NOVEL UREA DERIVATIVES CONTAINING NITROGENIC AROMATIC HETEROCYCLES
EP1112070B1 (en) 1998-08-20 2004-05-12 Smithkline Beecham Corporation Novel substituted triazole compounds
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
AU772477B2 (en) 1998-08-28 2004-04-29 Scios Inc. Inhibitors of p38-alpha kinase
JP4191825B2 (ja) 1998-09-10 2008-12-03 あすか製薬株式会社 ５−アミノイソキサゾール誘導体
JP2002526482A (ja) 1998-09-18 2002-08-20 バーテックス ファーマシューティカルズ インコーポレイテッド ｐ３８のインヒビター
DE19842833B4 (de) 1998-09-18 2005-04-14 Merckle Gmbh 2-Arylalkylthio-imidazole, 2-Arylalkenylthio-imidazole und 2-Arylalkinylthio-imidazole als Entzündungs-Hemmstoffe und Hemmstoffe der Cytokin-Freisetzung
AR023659A1 (es) 1998-09-18 2002-09-04 Vertex Pharma Un compuesto inhibidor de p38, una composicion farmaceutica que lo comprende y el uso de dicha composicion en el tratamiento y prevencion de estados patologicos
ES2211172T3 (es) 1998-09-25 2004-07-01 Astrazeneca Ab Derivados de benzamida y su utilizacion como inhibidores de citoquinas.
EE200100184A (et) 1998-09-25 2002-08-15 Boehringer Ingelheim Pharma Kg Uudsed asendatud indolinoonid inhibeeriva toimegamitmesugustele kinaasidele ja tsükliin/CDK kompleksidele
DK1117653T3 (da) 1998-10-01 2003-05-26 Astrazeneca Ab Quinolin- og quinazolinderivater og deres anvendelse som inhibitorer af cykokin-merierede sygdomme
AU1127700A (en) 1998-10-20 2000-05-08 Omeros Medical Systems, Inc. Irrigation solution containing mapk inhibitors and their use for treating pain and inflammation
AU6476599A (en) 1998-11-03 2000-05-22 Novartis Ag Anti-inflammatory 4-phenyl-5-pyrimidinyl-imidazoles
US6548503B1 (en) 1998-11-04 2003-04-15 Smithkline Beecham Corporation Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
ES2188254T3 (es) 1998-11-19 2003-06-16 Warner Lambert Co N-(4-(3-chloro-4-fluoro-fenilamino)-7-(3-morfolin-4-il-propoxi)-quin azolin-6-il)-acrilamada, un inhibidor irreversible de tirosina quinasas.
US6350744B1 (en) 1998-11-20 2002-02-26 Merck & Co., Inc. Compounds having cytokine inhibitory activity
CA2350081A1 (en) 1998-11-20 2000-06-02 G.D. Searle & Co. Process for making 5-substituted pyrazoles using dithietanes
ES2188280T3 (es) 1998-12-16 2003-06-16 Aventis Pharma Ltd Acetales heteroaril-ciclicos.
AU3114600A (en) 1998-12-16 2000-07-03 Vertex Pharmaceuticals Incorporated Crystallized p38 complexes
ES2244231T3 (es) 1998-12-25 2005-12-01 Teikoku Hormone Mfg. Co., Ltd. Derivados de aminopirazol.
CA2359244C (en) 1999-01-13 2013-10-08 Bayer Healthcare Llc .omega.-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors
UA73492C2 (en) 1999-01-19 2005-08-15 Aromatic heterocyclic compounds as antiinflammatory agents
GB9904933D0 (en) * 1999-03-04 1999-04-28 Glaxo Group Ltd Compounds
EP1163236B1 (en) 1999-03-12 2005-11-09 Boehringer Ingelheim Pharmaceuticals Inc. Aromatic heterocyclic compounds as anti-inflammatory agents
HUP0202248A3 (en) 1999-03-12 2006-06-28 Boehringer Ingelheim Pharma Compounds useful as anti-inflammatory agents
WO2000055153A1 (en) 1999-03-17 2000-09-21 Astrazeneca Ab Amide derivatives
RU2284187C2 (ru) 1999-03-17 2006-09-27 Астразенека Аб Производные амида, способы их получения, фармацевтическая композиция, способ лечения
GB9906566D0 (en) 1999-03-23 1999-05-19 Zeneca Ltd Chemical compounds
CO5170501A1 (es) 1999-04-14 2002-06-27 Novartis Ag AZOLES SUSTITUIDOS UTILES PARA EL TRATAMIENTO DE ENFERMEDADES MEDIADAS POR TNFa eIL-1 Y ENFERMEDADES DEL METABOLISMO OSEO
US6492516B1 (en) 1999-05-14 2002-12-10 Merck & Co., Inc. Compounds having cytokine inhibitory activity
SK16482001A3 (sk) 1999-05-21 2002-04-04 Scios Inc. Indolové deriváty ako inhibítory p38 kinázy
DE19924401A1 (de) 1999-05-27 2000-11-30 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
YU90901A (sh) 1999-06-21 2004-07-15 Boehringer Ingelheim Pharma Gmbh. & Co.Kg. Biciklični heterocikli, lekovi koji sadrže ta jedinjenja, njihova primena i postupci za njihovo pripremanje
US6403596B1 (en) 1999-06-28 2002-06-11 Merck & Co., Inc. Substituted pyridones having cytokine inhibitory activity
AU768878B2 (en) 1999-07-16 2004-01-08 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) Aminobenzophenones as inhibitors of IL-1beta and TNF-alpha
DK1210320T3 (da) 1999-07-16 2005-01-31 Leo Pharma As Aminobenzofenoner som inhibitorer for IL-1beta og TNF-alfa
PT1202957E (pt) 1999-07-16 2005-01-31 Leo Pharma As Aminobenzofenonas como inibidoras de il-1beta e tnf-alpha
ATE277897T1 (de) 1999-07-16 2004-10-15 Leo Pharma As Aminobenzophenone als inhibitoren von il-1beta und tnf-alpha
HUP0201910A3 (en) 1999-07-16 2006-03-28 Leo Pharm Prod Ltd Novel aminobenzophenones, pharmaceutical compositions containing them and their use
JP3952369B2 (ja) 1999-08-27 2007-08-01 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト 新規な置換インドリノン類、その製造及びその薬剤としての使用
US6762180B1 (en) * 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases
DE19949209A1 (de) 1999-10-13 2001-04-19 Boehringer Ingelheim Pharma In 5-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
UA75054C2 (uk) * 1999-10-13 2006-03-15 Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу
GB9924092D0 (en) 1999-10-13 1999-12-15 Zeneca Ltd Pyrimidine derivatives
AU7269600A (en) 1999-10-13 2001-04-23 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) A method of screening for substances acting on MSK1
PL357494A1 (en) 1999-10-21 2004-07-26 F.Hoffmann-La Roche Ag Alkylamino substituted bicyclic nitrogen heterocycles as inhibitors of p38 protein kinase
KR100523120B1 (ko) 1999-10-21 2005-10-20 에프. 호프만-라 로슈 아게 Ｐ38 단백질 키나제 저해제로서 헤테로알킬아미노-치환된이환 질소 헤테로환
RU2264403C2 (ru) 1999-11-10 2005-11-20 Орто-Макнейл Фармасьютикал, Инк. Замещенные 2-арил-3-(гетероарил) имидазо [1,2-а] пиримидины, содержащие их фармацевтические композиции и связанные с ними способы
UA74803C2 (uk) 1999-11-11 2006-02-15 Осі Фармасьютікалз, Інк. Стійкий поліморф гідрохлориду n-(3-етинілфеніл)-6,7-біс(2-метоксіетокси)-4-хіназолінаміну, спосіб його одержання (варіанти) та фармацевтичне застосування
MXPA02004879A (es) 1999-11-16 2002-08-30 Boehringer Ingelheim Pharma Derivados de urea como agentes antiinflamatorios.
US7053099B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
JP2003528043A (ja) 1999-11-23 2003-09-24 スミスクライン・ビーチャム・コーポレイション ＣＳＢＰ／ｐ３８キナーゼ阻害剤としての３，４‐ジヒドロ−（１Ｈ）キナゾリン−２−オン化合物
EP1248624A4 (en) 1999-11-23 2003-01-22 Smithkline Beecham Corp 3,4-DIHYDRO- (1H) -CHIRAZOLINE-2-ONES AND THE USE THEREOF AS CSBP / P38 KINASE INHIBITORS
WO2001038314A1 (en) 1999-11-23 2001-05-31 Smithkline Beecham Corporation 3,4-dihydro-(1h)quinazolin-2-one compounds as csbp/p38 kinase inhibitors
OA12097A (en) 1999-11-30 2006-05-04 Pfizer Prod Inc 2,4-Diaminopyrimidine compounds useful as immunosuppressants.
ATE362912T1 (de) 1999-12-06 2007-06-15 Leo Pharma As Aminobenzophenone als inhibitoren von il-1beta und tnf-alpha
US6602872B1 (en) 1999-12-13 2003-08-05 Merck & Co., Inc. Substituted pyridazines having cytokine inhibitory activity
ATE449764T1 (de) 1999-12-28 2009-12-15 Pharmacopeia Inc Cytokine, insbesondere tnf-alpha, hemmer
DE20002820U1 (de) 2000-02-16 2000-05-25 Igus Spritzgußteile für die Industrie GmbH, 51147 Köln Energieführungskette
WO2001062731A1 (en) 2000-02-23 2001-08-30 Iconix Pharmaceuticals, Inc. Pyridine-amidines as modulators of p38 map kinase
AU2001241927A1 (en) 2000-02-28 2001-09-12 Scios Inc. Inhibitors of p38-alpha kinase
AR035851A1 (es) 2000-03-28 2004-07-21 Wyeth Corp 3-cianoquinolinas, 3-ciano-1,6-naftiridinas y 3-ciano-1,7-naftiridinas como inhibidoras de proteina quinasas
CA2403152C (en) 2000-04-08 2008-10-28 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
DE10042058A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042062A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Hertellung
DE10042060A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042059A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10051320A1 (de) 2000-10-17 2002-04-25 Boehringer Ingelheim Pharma Neue Neurokininantagonisten, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen
DE10054019A1 (de) 2000-11-01 2002-05-23 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
US6638965B2 (en) 2000-11-01 2003-10-28 Boehringer Ingelheim Pharma Kg Substituted indolinones, preparation thereof and their use as pharmaceutical compositions
DE10063435A1 (de) 2000-12-20 2002-07-04 Boehringer Ingelheim Pharma Chinazolinderviate,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10117204A1 (de) 2001-04-06 2002-10-10 Boehringer Ingelheim Pharma In 6-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
EP1492536B1 (de) 2002-03-30 2012-05-09 Boehringer Ingelheim Pharma GmbH & Co.KG 4- ( n-phenylamino ) -chinazoline/chinoline als tyrosinkinaseinhibitoren
DE10233500A1 (de) 2002-07-24 2004-02-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylen]-6-methoxycarbonyl-2-indolinon-Monoethansulfonat und dessen Verwendung als Arzneimittel
US20040204458A1 (en) 2002-08-16 2004-10-14 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of Lck inhibitors for treatment of immunologic diseases
DE10237423A1 (de) * 2002-08-16 2004-02-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verwendung von LCK-Inhibitoren für die Behandlung von immunologischen Erkrankungen
US7148249B2 (en) 2002-09-12 2006-12-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Indolinones substituted by heterocycles, the preparation thereof and their use as medicaments
US20050043233A1 (en) 2003-04-29 2005-02-24 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis
PE20061155A1 (es) 2004-12-24 2006-12-16 Boehringer Ingelheim Int Derivados de indolinona como agentes para el tratamiento o la prevencion de enfermedades fibroticas
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
US20060154939A1 (en) 2004-12-24 2006-07-13 Boehringer Ingelheim International Gmbh Medicaments for the Treatment or Prevention of Fibrotic Diseases
MY158929A (en) 2008-06-06 2016-11-30 Boehringer Ingelheim Int Pharmaceutical combination

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
B�SRA �ZT�RK AKCORA ET AL: "Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation, angiogenesis and fibrosis in CCl4-induced liver fibrogenesis mouse model", SCIENTIFIC REPORTS, vol. 7, no. 1, 14 March 2017 (2017-03-14), XP55514197, DOI: 10.1038/srep44545 *
JINGANG HUANG ET AL: "Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis", ANNALS OF THE RHEUMATIC DISEASES, vol. 76, no. 11, 9 November 2017 (2017-11-09), pages 1941 - 1948, XP055514180, ISSN: 0003-4967, DOI: 10.1136/annrheumdis-2016-210823 *

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